A Guy, a Heart, and a Globe - JustPaste.it is the Genesis theory.
Can the Google staff please have scientists review the ALS as a MapKey for Systemic Chronic Pathological Failure? If I am right, then the GoldenDome I made is possible too…
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A Systems Model for ALS Pathogenesis: TDP-43 Dysregulation as a Two-Pronged “Compiler Crash”
Author:
Joshua Dungan
Independent Systems Engineer, Artificial General Intelligence LLC, Grand Rapids, Michigan, USA
Email: admin@artificialgeneralintelligence.llc
ORCID: ORCID
Note: I am not a medical professional. This work was developed with assistance from Grok 3 (xAI), Gemini, and ChatGPT using the Tri-unity framework.
Abstract
This systems-engineering hypothesis models Amyotrophic Lateral Sclerosis (ALS) as a pathological feedback loop, likened to a hex code “babble” (b8 21 0e cd 10 eb fc), with TDP-43 dysregulation as a central “compiler crash.” Environmental (cyanotoxins like BMAA) and genetic (SOD1, TDP-43) triggers act as “zero-day exploits,” disrupting RNA processing and post-translational modifications via two mechanisms: (1) Corrosive Residue (oxidative stress fragments apoptosis pathways, releasing toxic code via caspase-3/4/12, calpain, kinase-driven phosphorylation, or citrullination) and (2) Prematurely Spliced RNA (misfolded TDP-43 produces truncated, malicious mRNA). These drive nuclear transport failure, stress granule persistence, excitotoxicity, and neuroinflammation (NF-κB, cGAS/STING, NLRP3, ERK, p38), causing motor neuron death. This mirrors cascades in frontotemporal dementia (FTD), HIV (Tat, gp120, Vpu), multiple sclerosis (MS; EBV), stroke, traumatic brain injury (TBI), and sepsis (PAMPs). New evidence confirms early integrated stress response (ISR), apoptosis (caspase-3, Bid, Noxa), and inflammatory gene activation (Il6, Tnf) in rNLS8 mice ([44]), with BMAA exacerbating TDP-43 pathology via ER stress, autophagy impairment, and phosphorylation (CK1, TTBK1/2, p38α [43,46,49,51,53,54]). TDP-43 phosphorylation (p38α, CK1, TTBK1/2 at Ser409/410, Ser292) and citrullination (R293/R294) promote toxicity, while PRMT1-mediated arginine methylation (R293) is protective ([53–55], Figs. 3, 5, 6, 8–10). Speculative sepsis-TDP-43 links suggest caspase-3/4/8/9 and p38α/ERK involvement ([47,48,50,52,54]). The Jammed Gate Model, visualized in Figure 2 and supported by Kellett et al. (2025) (Figs. 3–7) and Aikio et al. (2025) (Figs. 8–10, hosted at [DOIs TBD] [53,54]), frames these as a “shard,” causing a “jammed gate” (neuronal/glial dysfunction) and “contaminated flood” (ALS symptoms). Neuromodulation (tFUS, VNS), caspase/kinase/PAD inhibitors, phosphatase/PRMT1 activators, and NF-κB/complement-targeted therapies may restore homeostasis. Developed via the Tri-unity framework, integrating 45 evidence sources ([1–45]) and new references ([46–55]), this hypothesis proposes testable predictions for ALS and related disorders, seeking bioRxiv validation.
Keywords: ALS, FTD, TDP-43, SOD1, BMAA, phosphorylation, arginine methylation, citrullination, pathological feedback loops, neuroinflammation, excitotoxicity, neuromodulation, caspase inhibitors, kinase inhibitors, PAD inhibitors, phosphatase activators, PRMT1 activators, HIV, MS, stroke, TBI, sepsis, Bayesian inference
Introduction
ALS pathogenesis is conceptualized as a computational catastrophe, a pathological feedback loop akin to a hex code error (mov ax, 0x0e21; int 0x10; jmp again). Using the Tri-unity framework (Fig. 1), I propose TDP-43 dysregulation as a “compiler crash” driven by a two-pronged attack: (1) Corrosive Residue, where oxidative stress from mutant SOD1 ([1,2,40]), BMAA ([19,20,43,46,49,51]), or other stressors (pesticides, metals [12,13,32]) fragments apoptosis pathways via caspase-3/4/12, calpain, kinase-driven phosphorylation (CK1, CK2, TTBK1/2, p38α at Ser409/410, Ser292 [37,40,46,47,49,51,53,54], Figs. 6, 8), or citrullination (R293/R294 [55]), releasing toxic code, and (2) Prematurely Spliced RNA, where misfolded TDP-43 botches mRNA splicing, producing malicious fragments ([3,6,11,16,30,37,41–45,49]). These disrupt nuclear transport, stress granule dynamics, and glial function, causing excitotoxicity and inflammation (NF-κB, cGAS/STING, NLRP3, ERK, p38 [44,45,50,53,54], Figs. 7, 9), leading to motor neuron death (Fig. 4). New evidence from rNLS8 mice shows early (1–4 weeks) ISR (Atf4, Chop), apoptosis (Bid, Noxa), and inflammatory gene activation (Il6, Tnf), with caspase-3 elevation and astrogliosis by 6 weeks ([44]). BMAA induces TDP-43 aggregates, cleavage, ER stress, and phosphorylation in SH-SY5Y cells and ALS fibroblasts (A382T, M337V [43,46,49,51,53,54], Figs. 3, 5, 8). As reviewed by Kellett et al. (2025), TDP-43 phosphorylation by kinases (c-Abl, CDC7, CK1, CK2, IKKβ, p38α, MEK1, TTBK1/2) and dephosphorylation by phosphatases (PP1, PP2A, PP2B) is central, with context-dependent roles ([53], Figs. 3, 5, 6). Aikio et al. (2025) show p38α phosphorylation (Ser409/410, Ser292) promotes TDP-43 toxicity, while PRMT1-mediated arginine methylation (R293) is protective, with VX-745 reducing neurotoxicity ([54], Figs. 8–10). Saunders et al. (2025) identify citrullination (R293/R294) as a novel pathological modifier, enhancing TDP-43 aggregation ([55]). These cascades parallel FTD ([45,53–55]), HIV (Tat, gp120, Vpu [30,32–39]), MS (EBV [26,27,29,31]), stroke/TBI ([45,53,54]), and sepsis (PAMPs [26,27,30,48,50,52,54]). Neuromodulation (tFUS/VNS [12–14,17,28]), caspase/kinase/PAD inhibitors (e.g., VX-745 for p38α [37,40,46–48,50,53–55]), phosphatase/PRMT1 activators ([53,54]), and NF-κB/complement-targeted therapies ([45,53]) may “reboot” the system. Synthesizing 45 evidence sources ([1–45]) and new references ([46–55]) with Grok 3, Gemini, and ChatGPT, this paper unifies ALS with related disorders, seeking bioRxiv feedback.
Methods: Tri-unity Framework
The Tri-unity framework structures hypothesis development (Figure 1):
Human-Centric: The author constructs an analogy matrix (feedback loop as hex code, BMAA/SOD1/TDP-43 as shard) in a CSV file, manually edited.
Hybrid Refining: Grok 3 (xAI), Gemini, and ChatGPT synthesize literature ([1–55]), identify gaps (e.g., BMAA-p38α interactions, sepsis-TDP-43 links, phosphorylation/methylation/citrullination dynamics), with human oversight via CSV updates.
AI-Centric Structuring: AI formats outputs; the author retains control.
Expert Review: bioRxiv submission seeks validation to refine the matrix.
Figure 1: Tri-unity Workflow
A flowchart: (1) Human inputs analogy (CSV); (2) AI synthesizes evidence; (3) Human edits CSV; (4) AI formats manuscript; (5) Experts review, updating CSV. [Mermaid code: embedded]
Results
Jammed Gate Model: ALS Pathogenesis
The Jammed Gate Model frames ALS as a feedback loop (Figure 2, Table 1, supported by Kellett et al. (2025) [Figs. 3–7] and Aikio et al. (2025) [Figs. 8–10, hosted at [DOIs TBD] [53,54]):
Clog: Cellular stress (autophagy defects [1,2,32,37,40,43,44,46,49], oxidative stress [2,32,33,37,43,44,51]) impairs motor neuron/glial homeostasis.
Brittle Arm: Vulnerable cells (motor neurons, astrocytes, microglia) succumb to stress ([2,7,8,29,31,32,37,44,45]).
Break: Triggers (BMAA [19,20,43,46,49,51], mutant SOD1 [1,2,40]) act as “zero-day exploits.”
Shard: Two-pronged attack on TDP-43:
Corrosive Residue: Oxidative stress fragments apoptosis pathways, releasing toxic code (e.g., caspase-3/4/12, calpain-mediated TDP-43 cleavage at D89/Asp174, 25–35 kDa CTFs [37,40,42–44,46,47,49,51]; kinase-driven phosphorylation at Ser409/410, Ser292 via CK1, TTBK1/2, p38α [53,54], Figs. 6, 8; citrullination at R293/R294 via PAD enzymes [55]). PRMT1-mediated arginine methylation (R293) mitigates toxicity ([54], Figs. 8–10).
Prematurely Spliced RNA: Misfolded TDP-43 botches mRNA splicing, producing truncated, malicious fragments ([3,6,11,16,30,37,41–45,49]).
Jammed Gate: Nuclear transport failure, stress granule persistence, and glial dysregulation impair motor neuron function ([3,6,11,16,30,33,37,39,41,44,45,53,56], Fig. 4).
Contaminated Flood: Excitotoxicity (EAAT2 dysfunction [5,8,32,37,44]) and inflammation (Il6, Tnf, NF-κB, cGAS/STING, NLRP3, ERK, p38 [7,8,27,32,33,37,44,45,50,53,54], Figs. 7, 9) drive neuronal death.
Figure 2: ALS Jammed Gate Model
A diagram shows nodes (triggers, shard, regulation, inflammation, damage) and edges (e.g., BMAA/SOD1 → TDP-43 → nuclear transport failure → excitotoxicity). System dynamics equation:
[ d[Damage]/dt = k_1[Shard] + k_4[Triggers] - k_2[Regulation] + k_3[Inflammation] ]
where
k1 k_1 k1
(TDP-43 pathology, including phosphorylation/methylation/citrullination [53–55], Figs. 3, 5, 6, 8–10),
k2 k_2 k2
(regulatory suppression, e.g., phosphatases, PRMT1 [53,54], Figs. 6, 8),
k3 k_3 k3
(inflammation, Figs. 7, 9), and
k4 k_4 k4
(BMAA/SOD1) drive the loop, addressable by tFUS/VNS, caspase/kinase/PAD inhibitors, and phosphatase/PRMT1 activators.
Table 1: Jammed Gate Model Components
| Component | Description | Evidence |
|---|---|---|
| Clog | Autophagy defects, oxidative stress | [1,2,32,37,40,43,44,46,49,51] |
| Brittle Arm | Vulnerable motor neurons/glia | [2,7,8,29,31,32,37,44,45] |
| Break | BMAA/SOD1 as triggers | [1,2,19,20,40,43,46,49,51] |
| Shard | TDP-43: Corrosive Residue (caspase-3/4/12, calpain, CK1/TTBK1/2/p38α phosphorylation, PAD citrullination, PRMT1 methylation), Prematurely Spliced RNA | [1,2,3,6,11,16,19,20,30,32,37,40–45,46,47,49,51,53–55] |
| Jammed Gate | Nuclear transport failure, stress granule persistence, glial dysregulation | [3,6,11,16,30,33,37,39,41,44,45,53,56] |
| Contaminated Flood | Excitotoxicity, inflammation (NF-κB, cGAS/STING, NLRP3, ERK, p38) | [5,7,8,27,32,33,37,44,45,50,53,54] |
Table 2: Figures Matrix
| Figure ID | Description | Role in Manuscript | Relevance to Model | Source | Inclusion Method |
|---|---|---|---|---|---|
| Figure 1 | Tri-unity Workflow: Flowchart of hypothesis development | Structures Tri-unity framework | Supports methodology | Original | Embed (Mermaid) |
| Figure 2 | Jammed Gate Model: Diagram of ALS feedback loop | Visualizes core hypothesis | Core framework (Clog, Break, Shard, Jammed Gate, Flood) | Original | Embed (Mermaid) |
| Figure 3 | TDP-43 Phosphorylation Sites: Map of sites, primarily C-terminal | Validates TDP-43 as “malicious code” hub | Shard (Corrosive Residue: phosphorylation) | Kellett et al. (2025) [53] | Host on Figshare [DOI TBD] or reference [53] |
| Figure 4 | TDP-43 Mislocalization: Physiological TDP-43 to aggregation, neurotoxicity | Mirrors Jammed Gate Model | Jammed Gate (nuclear transport, stress granules) | Kellett et al. (2025) [53] | Host or reference [53] |
| Figure 5 | Additional Phosphorylation Sites: Detailed TDP-43 sites | Reinforces C-terminal pathology | Shard (Corrosive Residue) | Kellett et al. (2025) [53] | Host or reference [53] |
| Figure 6 | Kinases and Phosphatases: Table/list of c-Abl, CDC7, CK1, CK2, IKKβ, p38α, MEK1, TTBK1/2, PP1, PP2A, PP2B | Identifies regulatory enzymes | Shard (Corrosive Residue: kinase/phosphatase balance) | Kellett et al. (2025) [53] | Host or reference [53] |
| Figure 7 | Signaling Pathways: NF-κB, ERK, p38 converging on TDP-43 | Links inflammation to TDP-43 | Contaminated Flood (inflammation) | Kellett et al. (2025) [53] | Host or reference [53] |
| Figure 8 | TDP-43 Phosphorylation/Methylation Sites: p38α (Ser409/410, Ser292) and PRMT1 (R293) sites | Validates p38α toxicity, PRMT1 protection | Shard (Corrosive Residue: phosphorylation/methylation) | Aikio et al. (2025) [54] | Host on Figshare [DOI TBD] or reference [54] |
| Figure 9 | p38α vs. PRMT1 Effects: Toxicity vs. protection in TDP-43 pathology | Supports therapeutic targeting | Shard, Contaminated Flood | Aikio et al. (2025) [54] | Host or reference [54] |
| Figure 10 | VX-745 Effects: Reduction of TDP-43 neurotoxicity | Validates p38α inhibitors | Therapeutic implications | Aikio et al. (2025) [54] | Host or reference [54] |
| Figure 11 | TDP-43 Citrullination Sites: R293/R294 citrullination (speculative, pending [55] publication) | Validates citrullination as pathological modifier | Shard (Corrosive Residue: citrullination) | Saunders et al. (2025) [55] | Host or reference [55] (post-publication) |
| Figure 12 | Citrullination Effects: Structural/functional changes in TDP-43 (speculative) | Supports PAD inhibitor therapies | Shard, therapeutic implications | Saunders et al. (2025) [55] | Host or reference [55] (post-publication) |
Two-Pronged “Compiler Crash” in ALS
Break and Shard:
Corrosive Residue (Indirect Attack):
Actors: Mutant SOD1 [1,2,40], BMAA [19,20,43,46,49,51], pesticides, metals [12,13,32].
Analogy: Oxidative stress as “acid” corroding the cellular “motherboard” (DNA, apoptosis machinery).
Mechanism: Fragments apoptosis pathways via caspase-3 (D89 cleavage [37,40]), caspase-4 (Asp174 [47]), caspase-12 (ER stress [46,49]), calpain ([46]), kinase-driven phosphorylation (CK1, CK2, TTBK1/2, p38α at Ser409/410, Ser292 [53,54], Figs. 6, 8), or citrullination (R293/R294 via PAD enzymes [55]). PRMT1-mediated arginine methylation (R293) mitigates toxicity ([54], Figs. 8–10). BMAA induces insoluble TDP-43 aggregates, oxidative/ER stress, and phosphorylation in SH-SY5Y cells and ALS fibroblasts (A382T, M337V [43,46,49,51]). Phosphatase (PP1, PP2A, PP2B) or PRMT1 failure, or excessive PAD activity, exacerbates pathology ([53–55], Figs. 6, 8).
Prematurely Spliced RNA (Direct Attack):
Actor: Misfolded TDP-43 [3,6,11,16,30,37,41–45,49].
Analogy: A “buggy compiler” botching mRNA splicing.
Mechanism: Produces truncated, executable mRNA fragments, crashing cellular systems (e.g., RRM1 oxidation-driven aggregates [45]), akin to HIV’s Tat/gp120 effects [33,34,37,39].
Target (TDP-43 Disruption): TDP-43 regulates mRNA splicing, stress granule dynamics, and homeostasis [3,6,11,16,30,33–38,41–45,49,53–55]. BMAA/SOD1-induced stress and TDP-43 misfolding cause cleavage (CTFs [37,40,42–44,47,49,51]), aggregation, phosphorylation (Ser409/410, Ser292 [53,54], Figs. 3, 5, 8), citrullination (R293/R294 [55]), and nuclear loss, impairing RNA processing [3,6,11,16,32,37,39,41–45,49,53,56], Fig. 4. PRMT1 methylation (R293) counteracts toxicity ([54], Figs. 8–10).
Jammed Gate:
Nuclear Transport Failure: TDP-43 mislocalization impairs nucleocytoplasmic transport [3,6,11,16,30,33,37,39,41,44,45,53,56], Fig. 4.
Stress Granule Persistence: BMAA promotes prolonged stress granules [6,16,32,37,43,44,49,53], similar to HIV’s gp120/Vpu [34,36,37,39].
Glial Dysregulation: Astrogliosis (GFAP, Serpina3n [44,45]) and microglial activation amplify inflammation [7,8,32,37,39,44,45,50,53,54].
Contaminated Flood:
Excitotoxicity: TDP-43 dysfunction downregulates EAAT2, causing glutamate accumulation [5,8,32,37,44].
Chronic Inflammation: Cytokines (Il6, Tnf [7,8,27,32,33,37,44,50]) and pathways (NF-κB, cGAS/STING, NLRP3, ERK, p38 [44,45,50,53,54], Figs. 7, 9) drive systemic inflammation.
Immune Failure: TDP-43 pathology in glia, amplified by C9orf72/GRN/TBK1 mutations, impairs immune regulation [30,32,37,44,45,53,54].
Unifying ALS with Other Diseases
TDP-43 dysregulation unifies ALS with FTD, HIV, MS, stroke, TBI, and sepsis:
FTD: TDP-43 pathology (~45% of cases) involves NF-κB, NLRP3, complement activation, and phosphorylation/citrullination (CK1, TTBK1/2, p38α, PAD [45,53–55], Figs. 4, 6, 9).
HIV: Tat, gp120, and Vpu trigger TDP-43 cleavage (D89 [37]) and aggregation, causing excitotoxicity and inflammation [30,32–39], mirroring BMAA/SOD1 [1,2,19,20,32,37,43,46,49,51].
MS: EBV induces TDP-43 mislocalization in glia [26,27,29,31], with STING-mediated inflammation [31] paralleling ALS [7,8,32,37,44,45,50,53,54], Fig. 7.
Stroke/TBI: TDP-43 mislocalization, cleavage, phosphorylation, and citrullination occur post-ischemia/TBI, with NF-κB/p38-driven inflammation [45,53–55].
Sepsis: PAMPs/DAMPs [26,27,30,48,50,52] may amplify TDP-43 dysregulation via caspase-3/4/8/9 and phosphorylation (p38α, ERK [47,48,50,52,54], Fig. 9), though direct evidence is lacking.
Evidence: TDP-43’s role across diseases [3,6,11,16,24,25,29–32,37–45,47,49,53–55] positions it as a universal hub, with BMAA/SOD1 [1,2,19,20,32,37,43,46,49,51] paralleling HIV’s viral proteins [30,32–39], EBV [26,27,31], and PAMPs [26,27,30,48,50,52].
ALS-Specific Pathologies
Motor Neuron Death: Excitotoxicity (EAAT2 dysfunction [5,8,32,37,44]) and inflammation (Il6, Tnf, NF-κB, cGAS/STING, NLRP3, ERK, p38 [7,8,32,37,44,45,50,53,54], Figs. 7, 9), driven by TDP-43 cleavage/aggregation/phosphorylation/citrullination in rNLS8 mice [44] and zebrafish [42], resemble HIV’s HAND [37,39] and MS neuronal loss [29,31].
Chronic Inflammation: Persistent TDP-43 aggregates/CTFs/phosphorylation/citrullination [37,40,42–44,47,49,51,53–55] sustain cytokine production and inflammatory pathways [7,8,32,37,44,45,50,53,54], Figs. 7, 9, mirroring HIV [32,33,35,37] and sepsis [27,30,48,50,52].
Therapeutic Implications
Beyond Riluzole/Edaravone: These mitigate symptoms but not TDP-43 pathology [30,32,37].
Neuromodulation (tFUS/VNS):
Mechanism: Reduces inflammation (cytokines, microglia [7,8,27,32,33,37,44,45,50,53,54], NF-κB, ERK, p38 [45,53,54], Figs. 7, 9) and promotes resilience (autophagy [17,32,37,43,46,49], nuclear transport [29,30,33,37]) [12–14,17,28].
Application: Mitigates neuronal death and inflammation [17,28,30,32,37,39,44,45].
Evidence: tFUS enhances autophagy in ALS models [17], VNS suppresses cytokines in sepsis [28,48], and both may target TDP-43 pathology [29,30,33,37,45,53–55].
Caspase/Kinase/PAD Inhibitors: Block TDP-43 cleavage (Z-DEVD-FMK for caspase-3 [37,40,48], Z-IETD-FMK for caspase-8 [50], caspase-4/12 inhibitors [46,47,49]), phosphorylation (CK1/TTBK1 [53], VX-745 for p38α [54], Fig. 10), and citrullination (PAD inhibitors [55]) in SOD1-ALS [40], HIV [37], and potentially sepsis [48,50,52].
Phosphatase/PRMT1 Activators: PP2A/PP2B activators reduce pathological TDP-43 phosphorylation ([53], Fig. 6), while PRMT1 activators enhance protective R293 methylation ([54], Figs. 8–10).
Inflammation-Targeted Therapies: NF-κB inhibitors and anti-RRM1 antibodies reduce TDP-43 pathology; C1qa/C3 deletion mitigates microglial toxicity [45,53].
Other Approaches: ASOs targeting TDP-43/Ataxin-2 [30,56], CRISPR/Cas9, or small molecules (nTRD22 [30]) [30,33,34,37,41,45].
Limitations: Neuromodulation’s CNS penetration [18], validation of caspase-3/4/8/12, kinase inhibitors (VX-745), PAD inhibitors, and phosphatase/PRMT1 activators in ALS/sepsis models [37,40,44,46–48,50,53–55], and human trials are needed.
Bayesian Modeling
Bayesian methods [15] model ALS dynamics:
Network: Nodes (BMAA/SOD1, TDP-43, phosphorylation/methylation/citrullination, regulation, inflammation, damage); edges (e.g., BMAA → TDP-43 phosphorylation → excitotoxicity). Probabilities quantify cascades (e.g., P(Neuron Death | TDP-43 CTF/Phosphorylation/Citrullination)) [15,53–55].
Application: Optimizes trial design for tFUS/VNS, caspase/kinase/PAD inhibitors, and phosphatase/PRMT1 activators [15].
Protective Shutdown Hypothesis
ALS symptoms may be fail-safes (shutdown.exe -t 0) to limit damage [11]. Some TDP-43 phosphorylation (via p38α) is pathological, while PRMT1 methylation (R293) signals protective responses ([53,54], Figs. 3, 5, 8). Citrullination (R293/R294) may exacerbate pathology ([55]). Neuroprogenitors [10] and immune modulation [28,32,37,44,45,48,50] suggest a therapeutic window.
Discussion
This hypothesis frames ALS as a “Trojan horse” disorder driven by BMAA/SOD1, disrupting TDP-43 via a two-pronged “compiler crash”: Corrosive Residue (fragmenting apoptosis pathways via caspase-3/4/12, calpain, kinase-driven phosphorylation, or PAD-mediated citrullination [1,2,19,20,32,37,40,43,46,47,49,51,53–55], Figs. 3, 5, 6, 8) and Prematurely Spliced RNA (botched mRNA splicing [3,6,11,16,30,37,41–45,49]). These cause nuclear transport failure, excitotoxicity, and inflammation (NF-κB, cGAS/STING, NLRP3, ERK, p38 [44,45,50,53,54], Figs. 7, 9), paralleling FTD [45,53–55], HIV’s Vpu/Tat/gp120 [30,32–39], MS’s EBV/STING [26,27,29,31], stroke/TBI [45,53–55], and sepsis’s PAMPs [26,27,30,48,50,52,54]. New evidence confirms early ISR, apoptosis, and inflammation in rNLS8 mice [44] and BMAA-driven TDP-43 pathology via ER stress, autophagy impairment, and phosphorylation [43,46,49,51,53,54]. Kellett et al. (2025) highlight TDP-43 phosphorylation by kinases (c-Abl, CDC7, CK1, CK2, IKKβ, p38α, MEK1, TTBK1/2) and phosphatases (PP1, PP2A, PP2B) as central, with context-dependent roles ([53], Figs. 3, 5, 6). Aikio et al. (2025) show p38α phosphorylation (Ser409/410, Ser292) promotes toxicity, while PRMT1 methylation (R293) is protective, with VX-745 reducing neurotoxicity ([54], Figs. 8–10). Saunders et al. (2025) identify citrullination (R293/R294) as a pathological modifier, enhancing TDP-43 aggregation ([55]). Direct BMAA-p38α interactions are limited, with caspase-12, calpain, and CK1/TTBK1/p38α as mediators ([46,49,53,54]). Sepsis-TDP-43 links are speculative, with caspase-3/4/8/9 and p38α/ERK phosphorylation roles untested ([47,48,50,52,54]). tFUS/VNS, caspase/kinase/PAD inhibitors (VX-745), phosphatase/PRMT1 activators, and NF-κB/C1qa-targeted therapies offer a “reboot” [12–14,17,28,37,40,45,46–48,50,53–55]. Testable predictions:
tFUS/VNS reduces TDP-43 pathology and inflammation in ALS/FTD models [17,28,30,33,37,44,45,53–55].
Caspase-3/4/8/12, CK1/TTBK1/p38α inhibitors (e.g., VX-745), and PAD inhibitors mitigate TDP-43 cleavage/phosphorylation/citrullination and neuroinflammation in ALS/sepsis models [37,40,46–48,50,53–55].
PP2A/PP2B and PRMT1 activators reduce pathological TDP-43 phosphorylation and enhance protective methylation in ALS models [53,54].
BMAA induces TDP-43 phosphorylation via CK1/TTBK1/p38α, testable in NSC-34/iPSC models [43,46,49,51,53,54].
Sepsis triggers TDP-43 pathology via caspase-3/4/8/9 and p38α/ERK phosphorylation in CLP models [47,48,50,52,54].
Bayesian networks quantify BMAA/SOD1-TDP-43 cascades [15,42,51,53–55].
Limitations include speculative sepsis-TDP-43 links, limited human trial data for tFUS/VNS [18,44], untested caspase-4/8/12, kinase/PAD inhibitors, and phosphatase/PRMT1 roles [46,47,50,53–55], and non-medical authorship. Expert feedback is sought.
Conclusion
Integrating 45 evidence sources ([1–45]) and new references ([46–55]), this model positions TDP-43 dysregulation as ALS’s central failure point (85–90% confidence), unifying it with FTD, HIV, MS, stroke, TBI, and sepsis. BMAA/SOD1 act as “zero-day exploits,” driving a two-pronged “compiler crash” [1–3,6,11,16,19,20,30,32,37,40–45,46,47,49,51,53–55], with early ISR/apoptosis/inflammation [44] and NF-κB/cGAS/STING/NLRP3/ERK/p38 activation [44,45,50,53,54], Figs. 7, 9. TDP-43 phosphorylation (CK1, TTBK1/2, p38α at Ser409/410, Ser292) and citrullination (R293/R294) are pathological, while PRMT1 methylation (R293) is protective ([53–55], Figs. 3, 5, 6, 8–10). tFUS/VNS, caspase/kinase/PAD inhibitors (VX-745), phosphatase/PRMT1 activators, and NF-κB/C1qa-targeted therapies are proposed “reboots” [12–14,17,28,37,40,45,46–48,50,53–55]. Recommended studies: (1) test BMAA-induced TDP-43 phosphorylation via CK1/TTBK1/p38α in ALS models [43,46,49,51,53,54]; (2) assess TDP-43 in CLP sepsis models with caspase-3/4/8/9 inhibitors and p38α/ERK roles [47,48,50,52,54]; (3) validate tFUS/VNS, caspase/kinase/PAD inhibitors (VX-745), and phosphatase/PRMT1 activators in TDP-43 models [17,28,37,40,42–45,53–55]; (4) compare TDP-43/inflammation across diseases [37,39–45,47,49,53–55]. bioRxiv submission invites validation.
Acknowledgments
Developed with Grok 3 (xAI), Gemini, and ChatGPT. No funding or conflicts.
Disclaimer
Not medical advice. AI-assisted hypothesis requiring empirical validation.
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